Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2TER5M)

• DOT Name: GTP-binding nuclear protein Ran (RAN)
• Synonyms: EC 3.6.5.-; Androgen receptor-associated protein 24; GTPase Ran; Ras-like protein TC4; Ras-related nuclear protein
• Gene Name: RAN
• Related Disease:
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Glaucoma/ocular hypertension
  Liver cancer
  OPTN-related open angle glaucoma
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Breast cancer
  Breast carcinoma
  Cardiac arrest
  Cervical Intraepithelial neoplasia
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epilepsy
  Esophageal squamous cell carcinoma
  Familial adenomatous polyposis
  Frontotemporal dementia
  HIV infectious disease
  Huntington disease
  Irritable bowel syndrome
  Keloid
  Laryngeal carcinoma
  Myotonic dystrophy
  Neoplasm
  Neuroblastoma
  Osteoporosis
  Prostate cancer
  Prostate carcinoma
  Rectal carcinoma
  Renal cell carcinoma
  Sciatic neuropathy
  Type-1/2 diabetes
  Fragile X-associated tremor/ataxia syndrome
  Lung cancer
  Lung carcinoma
  Pick disease
  Undifferentiated carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
  Mesothelioma
  Nasopharyngeal carcinoma
  Osteoarthritis
  Parkinson disease
  Plasma cell myeloma
  Venous thromboembolism
• UniProt ID: RAN_HUMAN
• PDB ID: 1I2M ; 1IBR ; 1K5D ; 1K5G ; 1QBK ; 1RRP ; 2MMC ; 2MMG ; 2N1B ; 3CH5 ; 3EA5 ; 3GJ0 ; 3GJ3 ; 3GJ4 ; 3GJ5 ; 3GJ6 ; 3GJ7 ; 3GJ8 ; 3GJX ; 3NBY ; 3NBZ ; 3NC0 ; 3NC1 ; 3ZJY ; 4C0Q ; 4GMX ; 4GPT ; 4HAT ; 4HAU ; 4HAV ; 4HAW ; 4HAX ; 4HAY ; 4HAZ ; 4HB0 ; 4HB2 ; 4HB3 ; 4HB4 ; 4OL0 ; 4WVF ; 5CIQ ; 5CIT ; 5CIW ; 5CJ2 ; 5CLL ; 5CLQ ; 5DH9 ; 5DHA ; 5DHF ; 5DI9 ; 5DIF ; 5DIS ; 5DLQ ; 5FYQ ; 5JLJ ; 5UWH ; 5UWI ; 5UWJ ; 5UWO ; 5UWP ; 5UWQ ; 5UWR ; 5UWS ; 5UWT ; 5UWU ; 5UWW ; 5YRO ; 5YST ; 5YSU ; 5YTB ; 5ZPU ; 6A38 ; 6A3A ; 6A3B ; 6A3C ; 6A3E ; 6CIT ; 6KFT ; 6LQ9 ; 6M60 ; 6M6X ; 6Q82 ; 6Q84 ; 6TVO ; 6X2M ; 6X2O ; 6X2P ; 6X2R ; 6X2S ; 6X2U ; 6X2V ; 6X2W ; 6X2X ; 6X2Y ; 6XJP ; 6XJR ; 6XJS ; 6XJT ; 6XJU ; 7B51 ; 7CND ; 7DBG ; 7L5E ; 7MNP ; 7MNQ ; 7MNR ; 7MNS ; 7MNT ; 7MNU ; 7MNV ; 7MNW ; 7MNX ; 7MNY ; 7MNZ ; 7MO0 ; 7MO1 ; 7MO2 ; 7MO3 ; 7MO4 ; 7MO5 ; 7YPZ ; 8HQ3 ; 8HQ6 ; 8UX1
• EC Number: 3.6.5.-
• Pfam ID: PF00071
• Sequence:
  MAAQGEPQVQFKLVLVGDGGTGKTTFVKRHLTGEFEKKYVATLGVEVHPLVFHTNRGPIK
  FNVWDTAGQEKFGGLRDGYYIQAQCAIIMFDVTSRVTYKNVPNWHRDLVRVCENIPIVLC
  GNKVDIKDRKVKAKSIVFHRKKNLQYYDISAKSNYNFEKPFLWLARKLIGDPNLEFVAMP
  ALAPPEVVMDPALAAQYEHDLEVAQTTALPDEDDDL
• Function: GTPase involved in nucleocytoplasmic transport, participating both to the import and the export from the nucleus of proteins and RNAs. Switches between a cytoplasmic GDP- and a nuclear GTP-bound state by nucleotide exchange and GTP hydrolysis. Nuclear import receptors such as importin beta bind their substrates only in the absence of GTP-bound RAN and release them upon direct interaction with GTP-bound RAN, while export receptors behave in the opposite way. Thereby, RAN controls cargo loading and release by transport receptors in the proper compartment and ensures the directionality of the transport. Interaction with RANBP1 induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins. RAN (GTP-bound form) triggers microtubule assembly at mitotic chromosomes and is required for normal mitotic spindle assembly and chromosome segregation. Required for normal progress through mitosis. The complex with BIRC5/survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2. Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.
• Tissue Specificity: Expressed in a variety of tissues.
• KEGG Pathway:
  Ribosome biogenesis in eukaryotes (hsa03008)
  Nucleocytoplasmic transport (hsa03013)
  Viral life cycle - HIV-1 (hsa03250)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  Regulation of cholesterol biosynthesis by SREBP (SREBF) (R-HSA-1655829)
  NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-168333)
  Nuclear import of Rev protein (R-HSA-180746)
  MicroRNA (miRNA) biogenesis (R-HSA-203927)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  tRNA processing in the nucleus (R-HSA-6784531)
  Postmitotic nuclear pore complex (NPC) reformation (R-HSA-9615933)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Altered Expression	[2]
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[3]
Liver cancer	DISDE4BI	Definitive	Altered Expression	[2]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiac arrest	DIS9DIA4	Strong	Biomarker	[8]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	Strong	Genetic Variation	[10]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[10]
Epilepsy	DISBB28L	Strong	Genetic Variation	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[12]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[13]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[14]
Huntington disease	DISQPLA4	Strong	Biomarker	[15]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[16]
Keloid	DISV09JY	Strong	Biomarker	[17]
Laryngeal carcinoma	DISNHCIV	Strong	Genetic Variation	[18]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Biomarker	[20]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[21]
Osteoporosis	DISF2JE0	Strong	Biomarker	[22]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[23]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[23]
Rectal carcinoma	DIS8FRR7	Strong	Genetic Variation	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[24]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[25]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[10]
Fragile X-associated tremor/ataxia syndrome	DISKB25R	moderate	Biomarker	[26]
Lung cancer	DISCM4YA	moderate	Altered Expression	[4]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[4]
Pick disease	DISP6X50	moderate	Biomarker	[6]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[27]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[27]
Mesothelioma	DISKWK9M	Limited	Biomarker	[28]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[29]
Osteoarthritis	DIS05URM	Limited	Biomarker	[30]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[31]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[32]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[33]

19 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GTP-binding nuclear protein Ran (RAN).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GTP-binding nuclear protein Ran (RAN).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GTP-binding nuclear protein Ran (RAN).	[36]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of GTP-binding nuclear protein Ran (RAN).	[37]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTP-binding nuclear protein Ran (RAN).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of GTP-binding nuclear protein Ran (RAN).	[39]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of GTP-binding nuclear protein Ran (RAN).	[40]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of GTP-binding nuclear protein Ran (RAN).	[41]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of GTP-binding nuclear protein Ran (RAN).	[42]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of GTP-binding nuclear protein Ran (RAN).	[43]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of GTP-binding nuclear protein Ran (RAN).	[44]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of GTP-binding nuclear protein Ran (RAN).	[45]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of GTP-binding nuclear protein Ran (RAN).	[46]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of GTP-binding nuclear protein Ran (RAN).	[48]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of GTP-binding nuclear protein Ran (RAN).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of GTP-binding nuclear protein Ran (RAN).	[50]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of GTP-binding nuclear protein Ran (RAN).	[46]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of GTP-binding nuclear protein Ran (RAN).	[51]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of GTP-binding nuclear protein Ran (RAN).	[44]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of GTP-binding nuclear protein Ran (RAN).	[47]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of GTP-binding nuclear protein Ran (RAN).	[49]

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